1. Field of the Invention:
This invention relates to an active agent delivery system for administering macromolecular polypeptide active agents having molecular weights of about 1000 or greater, particularly interferons, at a controlled rate for a prolonged period of time.
2. Background and Related Disclosures:
The traditional and most widely used method of administration of therapeutic agents is by the oral route. However, in the case of large polypeptides, such delivery is not feasible due to the hydrolysis of the peptides by digestive enzymes. The methods most commonly used for administration of polypeptide therapeutic agents are by repeated injection, intramuscular (IM), subcutaneous (SC) or intravenous (IV) infusion. These methods are acceptable in situations where a very limited number of injections are required, but are undesirable for chronic administration (for example as with insulin therapy). The nature of many of the diseases, disorders and conditions susceptible to improvement by polypeptide administration is chronic rather than acute, thus necessitating frequent injections over a prolonged period of time.
There is, therefore, a need for an efficacious and economical delivery system for large polypeptide agents. Biodegradable polymer matrices formed from polylactic acid or copolymers of polylactic acid with other comonomers such as polyglycolic acid have been used as sustained release delivery systems for a variety of active agents, due to their ability to biodegrade in situ. See, for example, U.S. Pat. Nos. 4,293,539, and 4,419,340. The use of these polymers in implants for delivery of several therapeutic agents has been disclosed in scientific publications and in the patent literature. See, for example, Anderson, L. C. et al, (1976), "An injectable sustained release fertility control system", Contraception 13: 375-384; Beck et al. (1979) "New long-acting injectable microcapsule contraceptive system", Am. J. Obstet. Gynecol. 140: 799-806; Yolles et al. (1978) "Timed release depot for anti-cancer agents II", Acta Pharm. Svec. 15: 382-388, U.S. Pat. No. 3,773,919, and U.S. patent application Ser. No. 699,715 filed Feb. 8, 1985. Sustained delivery of peptides from poly(lactide-co-glycolide) systems has been reported by Kent et al. (1982), "In vivo controlled release of an LHRH analog from injected polymeric microcapsules", Contracept. Deliv. Syst. 3: 58; by Sanders et al. (1984), "Controlled release of a luteinizing hormone-releasing hormone analogue from poly (d,l-lactide-co-glycolide)-microspheres", J. Pharmaceut. Sci. 73: 1294-1297, by T. Chang, "Biodegradeable semipermeable microcapsules containing enzymes, hormones, vaccines and other biologicals", J. Bioengineering, 1, 25-32 (1976), and in EPO Application No. 82300416.3, filed Jan. 27, 1982. However, the delivery of large polypeptides from polylactide matrices has been very difficult to achieve, for reasons that will be further discussed. Of the publications cited above, only the latter two disclose devices containing polypeptides having molecular weights of 2500 or greater.
Polylactide and poly(lactide-co-glycolide) polymers and copolymers (referred to generically hereinafter as polylactide or PLGA polymers) are not soluble in water. In contrast, most polypeptides are soluble in water but not in organic solvents. For this reason, the preparation of polylactide devices in which polypeptide particles are dispersed has, until now, generally followed one of two basic techniques. One technique involves mixing of the components with the polylactide in the molten state followed by heat extrusion, heat pressing, or casting. The second technique involves the creation of a solution/suspension of the polymer and polypeptide in an organic solvent, which is then pour-cast into a film or slab and the solvent evaporated. The latter method usually requires extensive or rapid stirring of the solution/suspension in order to achieve an acceptable degree of uniformity of the polypeptide particles and homogeneity of the polypeptide/polylactide matrix upon solidification. Evaporation of the solvent takes place over several hours to several days unless the film or slab is dried under vacuum, in which case bubbles are invariably created as the solid dries. Additionally, polylactide formulations prepared in this way are not sufficiently uniform for most therapeutic applications; due to coalescence of the water-soluble particle phase, the polypeptide is unevenly distributed within the polylactide as large aggregates of particles. Therefore, formulations prepared in this way must be submitted to further homogenization procedures such as grinding the formulation to a powder and reforming it under heat, or compressing or extruding the formulation under heat. The temperature required for these manipulations is usually at least 70.degree. C.
It is also known to make injectable microcapsules of drug in polylactide. Such microcapsules can be prepared by basic techniques such as that set out in U.S. Pat. No. 3,773,919, and in U.S. application Ser. No. 699,715. The latter method involves dissolving the polymer in a halogenated hydrocarbon solvent, dispersing the aqueous polypeptide containing solution by rapid stirring in the polymer-solvent solution, and adding a non-solvent coacervation agent which causes the polymeric excipient to precipitate out of the halogenated hydrocarbon solvent onto the dispersed polypeptide containing water droplets, thereby encapsulating the polypeptide. The resulting microcapsules are then dried by repeated organic solvent washings.
However, large polypeptides are particularly susceptible to physical and chemical denaturation and consequent loss of biological potency from exposure to excessive heat, solvents, and shear forces. For this reason, incorporation of large polypeptides in polylactide polymers has, until now, required either compromise in the degree of uniformity of the polypeptide/polymer dispersion, or has resulted in substantial loss of the biological potency of the polypeptide, or both. The resultant formulations are generally non-uniform dispersions containing irregularly sized large particles of polypeptide of reduced potency. The incorporation of large and irregular particles of polypeptide causes an uneven rate of drug delivery, and tends to exacerbate the multiphasic release profiles generally associated with polylactide pharmaceutical preparations.
Preparation of more homogenous monolithic formulations by known techniques, such as mixing of the molten components, grinding, and heat homogenation techniques such as compression and extrusion may result in a substantial, often nearly complete loss of biological activity of the polypeptide. For example, a PLGA/interferon formulation formed by heated mixing and extrusion under mild conditions retains less than 1% of the original biological activity of the interferon. (See Example 7, below.) To compensate for the loss in biological activity during manufacturing processes of this type, a large excess of polypeptide must be incorporated in the formulation.
A further disadvantage of formulations which contain denatured polypeptides is the increased immunogenicity which they exhibit. Antibody formation in response to the denatured polypeptide may partially or entirely contravene the desired therapeutic effect.
Accordingly, there is a need for a homogeneous polylactide device which provides controlled and regular delivery of macromolecular polypeptides and can be manufactured without significant loss of biological activity.